Ask the Expert: DMARDs and Opioids

Question: Can you mix DMARDs with opioids for rheumatoid arthritis?

According to the American College of Rheumatology, at least 1.3 million Americans suffer from rheumatoid arthritis (RA).1 Current guidelines recommend the use of disease-modifying antirheumatic drugs (DMARDs) for the treatment of RA symptoms, particularly for patients with low disease activity and those with moderate or high disease activity in the absence of poor prognostic features.2

DMARDs work by suppressing symptoms of active RA, such as joint pain and inflammation, and preventing bone erosions and joint space narrowing.3 Delaying DMARD therapy can lead to worsened physical functioning and progressive joint damage.3 Several DMARDs are indicated for RA, including hydroxychloroquine, leflunomide, methotrexate, minocycline, and sulfasalazine; these medications can be used alone or in combination to prevent RA disease progression.2,3 In spite of their many benefits, DMARDs are associated with adverse events (AEs) ranging from significant nausea and vomiting to more complex bone marrow, liver, and lung toxicities.3

Even when DMARD therapy is effective and has minimal AEs, many patients with RA continue to endure substantial pain.4 Patients traditionally have been prescribed non-steroidal anti-inflammatory drugs (NSAIDs) to minimize joint pain and inflammation. However, RA pain is multifactorial and can occur in the presence of non-inflammatory pain processes or irreversible joint damage.5 As a result, opioid use in this patient population has become more prevalent, and these agents have shown some benefit in controlling RA pain.

A systematic Cochrane Review evaluated the use of opioids in RA pain management. The review included randomized and quasi-randomized controlled trials comparing opioid therapy to another therapy (placebo or active control) in adult patients. The authors classified opioids as being ‘strong’ (morphine and fentanyl) or ‘weak’ (tramadol and codeine) based on World Health Organization classifications within the literature.6 Primary outcomes were efficacy and safety.

Eleven trials, comprising 672 patients with RA, met inclusion criteria. All the studies were of short duration (up to 6 wk) and the risk for bias was high in most of the studies. Most of the studies focused on ‘weak’ opioids; morphine was the only ‘strong’ opioid studied within the review. Six studies lasted for at least 1 week.

Five of the studies reported that opioid therapy was superior to placebo with respect to at least one efficacy measure. There were 3 studies that allowed for extraction of a patient-reported global efficacy measure. These studies, which were homogenous with respect to participant DMARD and NSAID use, showed opioids to be superior to placebo (relative risk [RR], 1.44; 95% confidence interval [CI], 1.03-2.03; number needed to treat, 6).6 However, pooled data from 4 studies examining the number of withdrawals due to inadequate analgesia showed no difference between the opioid and placebo groups (RR, 0.82; 95% CI, 0.34-2.01).6 In addition, the risk for AEs, such as nausea, dizziness, and constipation, was higher in the opioid group compared with the placebo group (odds ratio, 3.90; 95% CI, 2.31-6.56). AEs led to the withdrawal of 14.8% of the study participants overall.6

The reviewers concluded that there was limited evidence to support the regular use of weak opioids in the treatment of RA pain for 6 weeks or longer, and no evidence to support the use of strong opioids for any period. Although weak opioid use resulted in clinically significant pain improvement for up to 6 weeks, the risk for an AE also was significant. The reviewers pointed to the need for future studies focused on clinically relevant outcome measures to assess the benefits and risks of opioid use in patients with RA.

Evidence, Expertise, Exchange

In the meantime, clinicians can look at evidence-based recommendations for pharmacologic pain management in patients with inflammatory arthritis (IA) developed by Whittle et al. The 2010 3e (Evidence, Expertise, Exchange) Initiative recommendations were based on a systematic literature review and featured input from rheumatologists representing 17 countries. The panel concluded that short-term opioid use may have an acceptable risk-versus-benefit profile; however, caution was advised regarding long-term opioid use.7 Additionally, the lack of evidence surrounding strong opioid use, combined with the risk for AEs, indicated that strong opioids should be used only in cases of treatment failure and should be prescribed by clinicians experienced in pain management.

Several non-interventional studies have looked at the use of transdermal fentanyl for the treatment of RA pain. In 2 of these studies, a combined 266 patients with RA were treated with transdermal fentanyl. Both studies allowed for inclusion of patients receiving concurrent DMARD therapy. All the patients started at a dose of 25 mcg/h, and the dosage was titrated to ensure adequate pain control.8.9 Patients demonstrated statistically significant improvements in pain scores, functionality, and quality of life while receiving fentanyl. These results indicate the potential efficacy of strong opioids in RA patients with uncontrolled pain; however, both studies were of short duration and allowed the use of concurrent non-opioid analgesics.

In summary, the use of opioids may be beneficial in pain management for RA patients who are receiving DMARD therapy, but there are no long-term studies with definitive results to support their concurrent use. Patients and clinicians also should be aware of the risk for AEs related to use of DMARDs and opioids, and therapy should be regularly reviewed for efficacy and safety.

Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64(5):625-639.

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